DESCRIPTION: The overall objective of this proposal is to develop a fundamental understanding of the role of cavitation in LFS with an emphasis on its location, magnitude, effect on the skin structure and safety. The specific goals of this proposal include: 1. Understanding the precise role of cavitation in LFS: Specifically, identify: i) the location and magnitude of cavitation, ii) the type of cavitation (stable vs. transient), and iii) the fundamental mechanisms by which cavitation enhances transdermal transport. 2. Optimizing ultrasound parameters for LFS: Specifically, i) understand the dependence of the sonophoretic enhancement of critical ultrasound parameters, including frequency, intensity and pulse length, ii) understanding the dependence of cavitation on the same parameters and iii) use the knowledge gained on the dependence of the sonophoretic enhancement on ultrasound parameter to control and further optimize transdermal transport. 3. Assessing the long-term effects of cavitation on skin and drugs: Specifically, investigate: i) the reversibility of the changes in skin permeability, ii) the biological effects of low-frequency ultrasound, and iii) the effect of ultrasound on the stability of proteins that will be delivered transdermally. 4. Mathematical modeling of transdermal transport during LFS: Specifically, develop mathematical models to quantitatively predict the effect of ultrasound on transdermal transport and skin barrier recovery after sonophoresis.